G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias.
G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias.
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DOI：
10.1016/j.jbc.2022.102279
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发表时间：
2022-09
影响因子：
4.8
通讯作者：
Tesmer, John J. G.
中科院分区：
文献类型：
--
作者：
Chen, Qiuyan;Tesmer, John J. G.
G蛋白偶联受体（GPCR）激酶（GRK）和抑制蛋白与激动剂结合的GPCR相互作用，促进受体脱敏和下调。它们还触发不同于异源三聚体G蛋白的信号级联。有利于异源三聚体G蛋白或GRK/抑制蛋白信号传导的GPCR的偏性激动剂具有深远的药理学意义，因为它们可以带来副作用大大减少的新一代药物。可能发生偏向激动的一种机制是通过稳定优先结合GRKs和/或抑制蛋白的受体构象。在这篇综述中，我们探讨了这一想法，通过比较结构的GPCRs绑定到异源三聚体G蛋白与那些相同的GPCRs的复合物与抑制蛋白和GRKs。抑制蛋白和GRK复合物都表现出高度的构象异质性，这可能是它们适应和结合数百种不同GPCR的不寻常能力的结果。这种动态行为，沿着稳定GPCR复合物进行生物物理分析所需的实验策略，混淆了这些比较，但一些可能的偏倚分子机制开始出现。我们还研究了最近的结构是否以及如何推进我们对arrestins如何解析GRKs安装在GPCR的细胞内环和尾部的“磷酸化条形码”的理解。在未来，与完整的受体，具有明确的天然磷酸化条形码，如安装的两个非视觉亚家族的GRKs的arrestins在复杂的结构分析，将特别具有启发性。
G protein–coupled receptor (GPCR) kinases (GRKs) and arrestins interact with agonist-bound GPCRs to promote receptor desensitization and downregulation. They also trigger signaling cascades distinct from those of heterotrimeric G proteins. Biased agonists for GPCRs that favor either heterotrimeric G protein or GRK/arrestin signaling are of profound pharmacological interest because they could usher in a new generation of drugs with greatly reduced side effects. One mechanism by which biased agonism might occur is by stabilizing receptor conformations that preferentially bind to GRKs and/or arrestins. In this review, we explore this idea by comparing structures of GPCRs bound to heterotrimeric G proteins with those of the same GPCRs in complex with arrestins and GRKs. The arrestin and GRK complexes all exhibit high conformational heterogeneity, which is likely a consequence of their unusual ability to adapt and bind to hundreds of different GPCRs. This dynamic behavior, along with the experimental tactics required to stabilize GPCR complexes for biophysical analysis, confounds these comparisons, but some possible molecular mechanisms of bias are beginning to emerge. We also examine if and how the recent structures advance our understanding of how arrestins parse the “phosphorylation barcodes” installed in the intracellular loops and tails of GPCRs by GRKs. In the future, structural analyses of arrestins in complex with intact receptors that have well-defined native phosphorylation barcodes, such as those installed by the two nonvisual subfamilies of GRKs, will be particularly illuminating.
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影响因子：
64.8
作者：
Eichel K;Jullié D;Barsi-Rhyne B;Latorraca NR;Masureel M;Sibarita JB;Dror RO;von Zastrow M
通讯作者：
von Zastrow M
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1.8
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通讯作者：
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影响因子：
64.8
作者：
Kang Y;Zhou XE;Gao X;He Y;Liu W;Ishchenko A;Barty A;White TA;Yefanov O;Han GW;Xu Q;de Waal PW;Ke J;Tan MH;Zhang C;Moeller A;West GM;Pascal BD;Van Eps N;Caro LN;Vishnivetskiy SA;Lee RJ;Suino-Powell KM;Gu X;Pal K;Ma J;Zhi X;Boutet S;Williams GJ;Messerschmidt M;Gati C;Zatsepin NA;Wang D;James D;Basu S;Roy-Chowdhury S;Conrad CE;Coe J;Liu H;Lisova S;Kupitz C;Grotjohann I;Fromme R;Jiang Y;Tan M;Yang H;Li J;Wang M;Zheng Z;Li D;Howe N;Zhao Y;Standfuss J;Diederichs K;Dong Y;Potter CS;Carragher B;Caffrey M;Jiang H;Chapman HN;Spence JC;Fromme P;Weierstall U;Ernst OP;Katritch V;Gurevich VV;Griffin PR;Hubbell WL;Stevens RC;Cherezov V;Melcher K;Xu HE
通讯作者：
Xu HE
影响因子：
4.8
作者：
Komolov KE;Benovic JL
通讯作者：
Benovic JL